The ability to persistently alter synaptic strength lies at the root of brain learning systems, but the algorithms controlling these changes are still largely unknown. The hippocampus is a cortical brain structure involved in learning and memory, and a site where high-frequency firing of afferents produces long-term (LTP) of synaptic transmission. Recently, we have found that coactive, converging inputs to hippocampal pyramidal neurons can also elicit long-term depression (LTD) of synaptic strength, depending upon stimulus timing. We propose to determine the patterns of stimulation which elicit LTD, and explore the cellular mechanisms underlying LTD. Our studies will employ extra- and intracellular recording techniques in the in vitro hippocampal slice preparation. The objective of this proposal are: (1) determine the rules for induction of LTD, (2) determine whether alterations in excitatory and/or inhibitory transmission can explain LTD, and (3) identify neurotransmitter receptors mediating LTD. The long-range prediction is that knowledge of the physiological receptors mediating LTD. The long-range prediction is that knowledge of the physiological mechanisms controlling depression of synaptic transmission will be as important to our understanding of how learning occurs as mechanisms for enhancing synaptic efficacy. A better understanding of LTD mechanisms is likely to have wide impact in a number of clinical areas. LTD may be a mechanism to selectively forget, or block, storage of some memories, to improve recall of correct information. At the same time, any mechanism which dampens neuronal excitability is likely to be extremely important in preventing and controlling epileptic seizures, as well as limiting neuronal damage due to hyperexcitation. Furthermore, the persistent depression of synaptic strength may well be of great importance to retardation-associated learning defects.